Combinatorial synthesis of labelled drugs and PET tracers: synthesis of a focused library of 11C‐carbonyl‐labelled acrylamides as potential biomarkers of EGFR expression

Combinatorial synthesis is extensively used in drug development and lead optimisation. However, this approach has rarely been used for positron emission tomography because of limitations in available technologies. [11C]Carbon monoxide is amenable to combinatorial synthesis in transition‐metal‐catalysed reactions because it can react with a wide variety of electrophiles and nucleophiles, which opens up the possibilities for combinatorial radiochemistry. Herein, we exemplify the combinatorial approach by 11C‐labelling a library of epidermal growth factor receptor inhibitors. The selection of candidates was guided by molecular docking. Epidermal growth factor receptor is overexpressed in a variety of tumours, and it has become an important drug target. The 11C‐labelling reactions were performed using four substituted vinyl iodides and three different 4‐anilino‐6‐aminoquinazolines using a palladium‐mediated reaction with [11C]carbon monoxide using a single set of reaction conditions. In total, 12 labelled acrylamide derivatives were radiolabelled and obtained in 24–61% decay‐corrected radiochemical yield (from [11C]carbon monoxide). Starting from 5.6 GBq [11C]carbon monoxide, 0.85 GBq of formulated N‐[4‐(3‐bromo‐phenylamino)‐quinazolin‐6‐yl]‐acryl[11C]amide [11C]12da was obtained within 47 min from end of bombardment (specific activity of 60 GBq µmol−1). This strategy is an example of how [11C]carbon monoxide can be utilised in the labelling of libraries of drug candidates and positron emission tomography tracers for in vitro and in vivo testing.